AMYLOID ANGIOPATHY, EARLY PLAQUES & AGING

描述（改编自申请人的摘要）：自1983年以来，他们一直专注于 我们在家族性脑梗死中淀粉样蛋白沉积特征方面的努力， 不同来源的淀粉样血管病和定义其遗传缺陷。 遗传性脑出血伴淀粉样变性-Dutch型为首位 与淀粉样蛋白β前体突变相关的家族性形式 蛋白质基因随后，几个遗传异常的早期发病 已经分析了家族性阿尔茨海默病， 携带家族性阿尔茨海默氏症突变体的基因然而，无论是 荷兰的阿尔茨海默病动物模型已经阐明了 淀粉样蛋白生成与神经元功能障碍的关系。血管病变 缺血性损伤可能在脑缺血的发病机制中起重要作用 老年痴呆症是老年痴呆症与脑血管病的结合 梗塞是第二常见的痴呆类型。最近， 有机会分析一种新型痴呆症-家族性英国痴呆症（FBD） - 一种常染色体显性形式的脑血管淀粉样变性伴神经原纤维 退化导致进行性痴呆。我们证明了终止密码子 位于13号染色体上的一个新基因（BRI）的突变引起了一个新的突变， 延长的基因产物。这种异常的羧基末端的降解 前体分子释放一种34个氨基酸的淀粉样肽（ABri）， 在FBD患者的血管和实质斑块中沉积。 主要研究人员提出，ABri是主要原因， 神经退行性疾病和痴呆症的英国亲属，是一个理想的模型， 研究淀粉样蛋白生成、血管病理学和 神经变性目标一：（a）以生物化学和 用化学方法确定淀粉样蛋白沉积物的组成， 血管、血管周围和实质淀粉样斑块;（B）分离和 分析来自FBD的生物流体中的可溶性ABri物质及其前体 患者以及转染的细胞中。Tjeu博士还将确定 疾病是局部的或全身性的;（c）精确地描绘区域 负责通过不同长度的合成肽进行氟化， 混合物. 目的II：构建、开发和表征转基因小鼠模型， 联邦调查局

DESCRIPTION (adapted from applicant's abstract):Since 1983 they have focused our efforts in the characterization of amyloid deposition in familial cerebral amyloid angiopathies of different origin and in defining their genetic defects. Hereditary cerebral hemorrhage with amyloidosis-Dutch type was the first familial form to be associated with mutations of the amyloid beta precursor protein gene. Subsequently, several genetic abnormalities in early onset familial Alzheimer's disease have been analyzed and transgenic mouse models carrying familial Alzheimer's mutants have been developed. However, neither the Dutch type nor animal models of Alzheimer's disease have clarified the relationship between amyloidogenesis and neuronal dysfunction. Vascular lesions and ischemic damage may play an important role in the pathogenesis of Alzheimer's disease since a combination of Alzheimer's disease and cerebral infarction is the second commonest type of dementia. Very recently we had the opportunity to analyze a new type of dementia - familial British dementia (FBD) - an autosomal dominant form of cerebrovascular amyloidosis with neurofibrillar degeneration leading to progressive dementia. We demonstrated that a stop codon mutation of a novel gene (BRI) localized on chromosome 13 gave rise to an elongated gene product. Degradation of the carboxyl-end of this abnormal precursor molecule releases a 34 amino acid amyloid peptide (ABri) found deposited in vascular and parenchymal plaques in patients with FBD. The principal investigators propose that ABri is the main cause of neurodegeneration and dementia in the British kindred and is an ideal model to study the relationship between amyloidogenesis, vascular pathology, and neurodegeneration. They plan: Aim I: (a) to biochemically and immunohistochemically define the composition of the amyloid deposits in vascular, perivascular, and parenchymal amyloid plaques; (b) to isolate and analyze soluble ABri species and its precursor(s) in biological fluids from FBD patients as well as in transfected cells. Dr Tjeu will also determine whether the disease is localized or systemic; (c) to precisely delineate the region(s) responsible for fibrillization via synthetic peptides of different length and composition. Aim II: to construct, develop and characterize a transgenic mouse model for FBD.